Project 4 of this Program Project is concerned with changes in the central nervous system that follow peripheral nerve injury. We will use an experimental mononeuropathy model in rat, and subsequently in monkey, which leads to pain behavior in the animals characterized by abnormal posture of the affected limb and exaggerated responses to innocuous stimuli (allodynia) as well as to noxious stimuli (hyperalgesia). Several investigators have shown that partial ligation of the sciatic nerve of the rat leads to degeneration of substantial populations of myelinated and of nonmyelinated axons in the nerve. In a pilot study we have shown that at 14 days postligature there is extensive axonal and synaptic degeneration in the dorsal horn of the rat spinal cord, during a period in which the animal exhibits pain behavior. Other studies have suggested that there is impaired inhibitory circuitry in the dorsal horn of such animals. We will use axon transport combined with immunocytochemical, electron microscopic techniques to examine the circuitry of the dorsal horn at various times following peripheral nerve injury as the pain-related behavior is first manifested until it gradually wanes over a two-month period. Our working hypothesis is that pain behavior can be correlated with changes in the dorsal horn, particularly in the GABAergic circuitry at various survival times. The second major aspect of the study is an examination of the projections of spinothalamic tract ells in the affected segments to the thalamus, the working hypothesis being that there are changes in circuitry in the thalamus that can be correlated with changes in pair behavior, particularly in the monkey. We have previously shown that there is a distinct difference between systems that convey pair information, as well as systems that convey information about innocuous stimuli, in the primate thalamus. We suggest that the thalamic circuitry receiving input from affected spinal segments will be modified as a consequence of the peripheral nerve injury. In humans, pain is often a consequence of peripheral nerve injury and out studies proposed here may lead to a design of rational therapies based upon an understanding of alterations in neural circuitry of the spinal cord and thalamus after peripheral nerve injury. In particular, we hypothesize that the inhibitory circuitry of the cord and thalamus is subject to changes following nerve injury and as we better understand the reorganization of the nervous system that takes place following peripheral nerve injury, improved pharmacological therapies designed to address these changes may ultimately be developed.